With the advancement of modern medicine, the population of elderly people around the world is increasing, and as a result, the number of patients with dementia which is geriatric diseases is increasing rapidly. Alzheimer's disease is the most common form of dementia and is a progressive neurodegenerative disorder characterized by memory loss, cognitive and behavioral stability. Although the cause of the onset of the disease is not clearly known yet, as a result of brain tissue analysis after death, an accumulation of amyloid plaques composed of beta-amyloid peptide (Aβ) between neurons and neurofibrillary tangles formed by hyperphosphorylated tau protein filaments in neurons have been reported [Ginsberg S D et al., Kluwer Academic/Plenum: New York, 1999: pp 603-654; Lee V M et al., Neuron 1999; 24:507-510; Selkoe D J. JAMA 2000; 283: 1615-1617]. 39 to 43 amino acids including the Aβ peptide are derived from the larger amyloid precursor protein (APP). In the production pathway of amyloid, The Aβ peptide is cleaved from APP by sequential proteolysis of β- and γ-secretase. The Aβ peptide is released as a soluble protein and can be detected at low levels in cerebrospinal fluid (CSF) in the normal aged brain. During the course of Alzheimer's disease, it has been found that Aβ peptides are aggregated and form amyloid deposits in the brain or blood vessels [Blennow et al., Lancet. 2006 Jul. 29; 368(9533):387-403]. In addition, it is known that amyloid deposits play a role in amyloidosis where amyloid proteins are abnormally deposited in different organs and/or tissues and cause disease [Chiti et al., Annu Rev Biochem. 2006; 75: 333-66].
Accordingly, for the diagnosis of diseases including Alzheimer's disease that can be diagnosed by quantitatively detecting amyloid aggregates, a number of studies have been conducted on fluorescent compounds that bind well to the beta amyloid aggregate and easily indicate its presence. A representative of these compounds is Congo red (CR), and a definite diagnosis of Alzheimer's disease is possible by performing an autopsy and then staining the brain with the Congo red. However, the Congo red has a disadvantage that it has strong water solubility and cannot pass through the brain blood barrier (BBB), so it cannot enter the brain even if administered to a living person. In addition to the Congo red, one of the first compounds developed is derivatives of Chrysamine-G, but this also was passed through the brain blood barrier at low levels and thus could not actually have been used [Klunk W E, et al., Neurobiol Aging 1994; 15:691-8. Klunk W E, et al., Neurobiol Aging 1995; 16:541-8]. Subsequently, derivatives of 6-dialkylamino-2-naphthylethenylidene (FDDNP) and thioflavin-T (ThT) based derivatives have been developed [Agdeppa E D, et al., J Neuroscience 2001; 21:1-5; Mathis C A, et al., Bioorg Med Chem Lett 2002; 12:295-298.]. In addition, various benzothiazole derivatives and stilbene derivatives have been filed for the patent as a radioisotope labeling compound capable of imaging beta amyloid [US 2002/0133019 A1, US 2003/0149250 A1].
Previously developed fluorescent ligands for the detection of beta amyloid have a complex manufacturing process, have a large molecular weight and did not show significant changes in fluorescence properties after binding to beta amyloid aggregate. In addition, since there was a drawback in that the previously developed fluorescent ligand selectively binds not only specifically to beta amyloid but also to phosphorylated tau protein fibers, they do not have high detection selectivity, but also have low absorption in animal experiments, and it is not easy to remove the ligand from the brain, thus it has been difficult to actually use. Accordingly, there is a continuing need for the development of reagents useful for overcoming the problems of the conventional beta-amyloid detecting ligands and specifically detecting and imaging only amyloid aggregates.
It is known that the curcumin is the main ingredient of curry, an Indian staple food, and the incidence of Alzheimer's disease among Indian elderly people aged 70-79 years is 4.4 times lower than that of Americans [Arch. Neurol. 2000; 57:824-830]. This suggests the potential for the curative effect of curcumin in the prevention and treatment of Alzheimer's disease. In fact, according to recent literature, when curcumin was injected into transgenic mice with amyloid accumulation, the curcumin bound to the plaque through the blood-brain barrier. When curcumin was fed to transgenic mouse, amyloid levels and plaque levels were reduced [J. Biol. Chem. 2005; 18:5892-5901]. Also, the curcumin has been reported to have safety due to low toxicity [J. Neurosci. 2001; 21: 8370-8377; Anticancer Res. 2001; 21: 2895-2900]. Studies have been conducted to predict the effects on the prevention and treatment of dementia in mouse by performing passive avoidance test or Y-maze test in the mouse using curcumin or its derivatives and oleoresin turmeric extract [Korean patent application nos. 2001-0013726 and 2001-0023065]. In addition, new curcumin derivatives such as hydrazinocurcumin have been used for antiangiogenic activity studies [Korean patent application no. 2005-0010058].
Meanwhile, photo-acoustic imaging based on photo-acoustic effects has attracted much attention as a biomedical imaging modality that provides biological information by visualizing intrinsic biological molecules such as melanin and hemoglobin. The high potential of photo-acoustic imaging as biomedical imaging is being accelerated by the development of exogenous contrast agents based on the photo-acoustic response of nanomaterials, in terms of diagnosis and treatment that encompass real-time and targeted imaging with high sensitivity, multi-mode imaging and image-guided therapy.
In this regard, the development of suitable nanoprobes that exhibit photo-acoustic effects is an important technical issue in nanotechnology to improve the efficiency of photo-acoustic imaging and optimize a variety of biomedical applications. Further, the development and artificial manipulation of nanoprobes that exhibit photo-acoustic effects can provide another important insight into the fundamental understanding of photo-acoustic imaging based on nanomaterials. In principle, the photo-acoustic effect is due to the generation of sound waves through the absorption of short-pulsed radiation which locally heat the target, thereby resulting in thermal expansion. Although the extinction coefficient and the conversion efficiency of absorbed photons into heat are the major factors that generate photo-acoustic signals in photo-acoustic imaging based on nanomaterials such as molecular level absorbers, the surface environment of nanomaterials provides another parameter that determines the efficiency of the photo-acoustic effect. Since photo-acoustic effects accompanied by thermal expansion are generated from the locally heated surrounding medium through thermal conversion from nanomaterials to the surrounding medium, the surface environment associated with thermal transfer and divergence dynamics is a sensitive factor that produces photo-acoustic effects based on nanomaterials.
Accordingly, the development and manipulation of new forms of photo-acoustic diagnostic agents for a basic understanding of the photo-acoustic response based on the new photo-acoustic diagnostics can provide important clues for devising and optimizing contrast agents that cause photo-acoustic imaging.
Therefore, the inventors of the present invention have confirmed that the curcumin derivative represented by formula 1 according to the present invention may be useful as a composition for the detection of beta-amyloid and diagnosis of diseases due to excessive production of beta-amyloid, while studying compounds which have excellent selective binding force to beta-amyloid, can be detected by optical imaging or photo-acoustic imaging methods and in particular are capable of detecting high photo-acoustic signals in response to irradiation of light of a particular wavelength range, and have completed the present invention.